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Subjects

Abstract

The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

Acknowledgements

This work is supported by the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow (103858/Z/14/Z). L.R.Y., Y.L. and L.B.A. are funded by Wellcome Trust PhD fellowships. S.N.-Z. is funded by a Wellcome Trust Intermediate Clinical Research Fellowship (WT100183MA). P.V.L. is a postdoctoral researcher at the Research Foundation Flanders (FWO). Work within the project is supported by the Belgian Cancer Plan–Ministry of Health, the Breast Cancer Research Foundation, the Brussels Region, the Norwegian Cancer Society, the Norwegian Health Region West and the Bergen Research Foundation. Some samples referenced in this publication will be included in the Breast Cancer Genome Analyses for the International Cancer Genome Consortium (ICGC) Working Group led by the Wellcome Trust Sanger Institute. BASIS is a part of the ICGC working group and is funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under grant agreement number 242006. This working group also encompasses a triple-negative breast cancer project funded by the Wellcome Trust (grant 077012/Z/05/Z) and a HER2+ breast cancer project funded by Institut National du Cancer (INCa). We thank B. Leirvaag, D. Ekse, N.K. Duong and C. Eriksen for technical assistance. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy.

Author information

Affiliations

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.

Lucy R Yates

, Moritz Gerstung

, Gunes Gundem

, Peter Van Loo

, Ludmil B Alexandrov

, Helen Davies

, Yilong Li

, Young Seok Ju

, Manasa Ramakrishna

, Serena Nik-Zainal

, Stuart McLaren

, Adam Butler

, Sancha Martin

, Dominic Glodzik

, Andrew Menzies

, Keiran Raine

, Jonathan Hinton

, David Jones

, Laura J Mudie

, Michael R Stratton

, David C Wedge

& Peter J Campbell

Department of Oncology, The University of Cambridge, Cambridge, UK.

Lucy R Yates

Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.